Characterisation and Genetic Architecture of Major Depressive Disorder Subgroups Defined by Weight and Sleep Changes

Major depressive disorder, MDD, is highly heterogeneous and thus subgroups with different underlying aetiologies have been postulated. The aim of this work is to further characterise depression subgroups defined using sleep and weight changes. Probable lifetime MDD cases (n = 26,662) from the UK Biobank were stratified into three subgroups defined by self-reported weight and sleep changes during worst episode: (i) increased weight and sleep (↑WS), (ii) decreased weight and sleep (↓WS) and (iii) the remaining uncategorised individuals. Analyses compared the depression characteristics, mental health scores, neurological and inflammatory comorbidities and genetic architecture between subgroups and with 50,147 controls from UK Biobank. In contrast to ↑WS depression, ↓WS depression had a higher age of onset and lower proportion reporting countless or continuous episodes compared to uncategorised individuals. The ↓WS depression also had a higher wellbeing score than the other subgroups. Analyses of subgroup comorbidities identified a novel association between ↑WS depression and epilepsy. Subgroup-specific GWAS identified three genome-wide significant loci associated with ↑WS in genes previously associated with immunometabolic traits and response to anticonvulsants. The effect of BMI adjustment in the genetic analyses of the subgroups and using broader weight-only definitions were also examined. The findings provide further evidence for differences in the characteristics and genetic architecture of depression subgroups defined by sleep and weight change and highlight the importance of dividing non-↑WS individuals into ↓WS and uncategorised subgroups in analyses, as ↓WS symptoms may identify a more acute depression subgroup.